“Time is running out”
Studying an animal model for the development of dementia: Christian Haass at his zebrafish “farm”. (Photo: C. Olesinski)
Last month the pharmaceuticals giant Pfizer decided to discontinue a large-scale clinical study of a candidate drug for the treatment of Alzheimer’s disease, when it became obvious that the compound had no effect on the condition. What went wrong?
Christian Haass: That this trial failed is not very surprising. The study was done on patients who likely had already undergone loss of neural tissue in the brain when they joined the trial. In other words, the Tus the treatment simply came too late, perhaps years too late.
Two years ago, the Eli Lilly company was also forced to break off a similar trial. The therapeutic benefits in that study were negligible, and the test substance had serious side-effects.
In that case, it was known that the drug candidate, an enzyme inhibitor, had a potent effect on differentiating cells, so there was an obvious risk of serious side-effects. However, the notion has arisen that all these new compounds can’t work in principle, and that researchers are on the wrong track with their theories of how the disease comes about. Some of the media have already accused us researchers of falling down on the job. That picture is totally false and misleads the public.
What exactly causes the disease?
The protein deposits that are characteristic for dementia, the so-called plaques, are aggregates of smaller toxic proteins called amyloid. These are derived from a larger membrane protein by the action of enzymes that work like molecular scissors. When amyloid fragments are excised from the precursor, they rapidly begin to form clumps that eventually kill nerve cells.
Which form is actually responsible for the neurotoxicity, the amyloid fragment itself, the intermediate aggregates or the plaques?
Most likely they all work together in a pathological cascade. It begins with the release of the amyloid, which disrupts internal biochemical processes when it comes into contact with nerve cells. For instance, it interferes with the function of synapses, which are responsible for the transmission of signals from one nerve cell to another. - Or it induces the disintegration of intracellular filaments that serve as highway systems, releasing so-called tau proteins which themselves form clumps. I now believe that the amyloid only provides the initial impetus that sets off the whole avalanche which ultimately leads to the death of the cell.
So you are convinced that the amyloid hypothesis is correct?
Yes, certainly. Recent studies in Iceland have confirmed it once and for all. In the early 1990s when I was working together with Martin Citron and Dennis Selkoe at Harvard we described the effect of a mutation responsible for the hereditary form of Alzheimer’s. This mutation changes the structure of the precursor protein near the point of cleavage in such a way that it is easier for the scissors to liberate the amyloid. The result is that more amyloid is produced, and the disease emerges at an earlier age. All the familial Alzheimer mutations discovered since act in a similar fashion. The new work from Iceland describes a mutation that has the opposite effect. It reduces the rate of amyloid production, because a different change at the same site makes it less accessible to the scissors. - And this mutation seems to protect its carriers from Alzheimer’s. Geneticists have been screening the Icelandic population on a large scale for some years now, and this variant turned up in the genomes of elderly people who show no signs of dementia. Indeed, the normal cognitive decline that occurs in old age seems to be delayed in this group.
Are there any promising candidate therapeutics in the pipeline? There is nothing on the market at the moment that really does any good.
By far the most promising approach is passive immunization with an antibody. The principle is the following. One injects into the bloodstream an antibody that is specific for the amyloid. When the antibody gets to the brain, it recognizes and binds to the amyloid, enabling the immune system to home in on the complex and destroy it. Properly designed experiments are now underway to test its effect. As a rule, dementia develops spontaneously at an advanced age. However, in a small fraction of cases, Alzheimer’s disease is genetically determined, and becomes manifest in an aggressive form by the age of 40 - 60. In these cases, the causative mutations are known, and one can predict precisely who will develop the disease and who won’t. At present, carriers of these mutations have no chance to escape the consequences. For this reason, I believe it is ethically justifiable, indeed incumbent on us, to offer these people a prophylactic, experimental therapy before they begin to show symptoms of the disease. And many of them are quite willing to take part in such a study. Preparations for a trial of this kind are already underway worldwide, and the German Center for Neurodegenerative Diseases (DZNE), whose Munich branch I direct, is among the institutions involved in organizing it.
But presumably, in order to be effective against senile dementia, a vaccine would have to be administered early, and everyone would have to be immunized.
Yes, it would be best to inoculate the population prophylactically, like we once did to protect against polio. That would probably be possible with the antibodies we now have. The real problem is how one might design a study that could rule out long-term side-effects. I have no idea how to resolve this dilemma, but the demographic situation tells me that time is running out, and a great deal is expected of us.
In the Excellence Initiative, your proposal for the Synergy Cluster, an interdisciplinary research network, was approved for funding. The new cluster will provide opportunities to study Alzheimer’s within a broader context. Can you explain the thinking behind this?
We want to get away from the approach that looks at a single pathological mechanism in isolation, as my laboratory has been studying the – degenerative – amyloid cascade. Every Alzheimer’s patient also has problems with cerebral blood flow. And we know from the devastating effects of strokes where that can lead; there are obvious parallels. That is why a stroke researcher like Martin Dichgans is involved in the cluster, and his team and my group will be moving into a new building together soon. Furthermore, as far as I know, there isn’t a single Alzheimer’s patient who doesn’t display signs of severe inflammation in the brain. At the moment, it is impossible to say whether this is a defense mechanism or actually exacerbates neurodegeneration. So we also have neuroimmunologists in our Synergy Cluster. This integrated, holistic view of the disease is what is really new.